C-C chemokine receptor 5 signaling contributes to cardiac remodeling and dysfunction under pressure overload

Abstract

Aortic stenosis (AS) leads to chronic pressure overload, cardiac remodeling and eventually heart failure. Chemokines and their receptors have been implicated in pressure overload-induced cardiac remodeling and dysfunction. In the present study, the role of C-C chemokine receptor 5 (CCR5) in pressure overload-induced cardiac remodeling and dysfunction was investigated in mice subjected to transverse aortic constriction (TAC). Cardiac levels of CCR5 and C-C motif chemokine ligands (CCLs)3, 4 and 5 were determined by western blotting and reverse transcription-quantitative PCR, respectively. Cardiac functional parameters were evaluated by echocardiographic and hemodynamic measurements. Myocardial fibrosis was assessed by Masson's trichrome staining and α-smooth muscle actin immunostaining. Myocardial hypertrophy and inflammatory cell infiltration were evaluated by hematoxylin and eosin staining. Angiotensin II (Ang II)-induced hypertrophy of H9c2 cardiomyocytes was assessed by F-actin immunostaining. ERK1/2 and P38 phosphorylation was examined by western blotting. TAC mice exhibited higher myocardial CCL3, CCL4, CCL5 and CCR5 levels compared with sham mice. Compared with sham mice, TAC mice also exhibited impaired cardiac function along with myocardial hypertrophy, fibrosis and inflammatory cell infiltration. TAC-induced cardiac remodeling and dysfunction were effectively ameliorated by administration of anti-CCR5 but not by IgG control antibody. Mechanistically, increased ERK1/2 and P38 phosphorylation was detected in TAC hearts and Ang II-stimulated H9c2 cardiomyocytes. Treatment with anti-CCR5 antibody decreased ERK1/2 and P38 phosphorylation and attenuated Ang II-induced H9c2 cell hypertrophy. CCR5 inhibition protected against pressure overload-induced cardiac abnormality. The findings of the present study indicate that ERK1/2 and P38 signaling pathways may be involved in the cardioprotective effects of CCR5 inhibition.

The E3 ubiquitin ligase WWP2 regulates pro-fibrogenic monocyte infiltration and activity in heart fibrosis

“…Ex vivo isolated cardiac macrophages following Ang-II-infusion, showed a dramatic increase in Ccl5 expression which was reduced in WWP2 Mut/Mut animals. Ccl5 is critical for macrophage recruitment and infiltration to tissues 56,[85][86][87] , and the CCL5-mediated macrophage recruitment associates with myocardial infarction 88 and cardiac dysfunction 89 . Our results do not suggest a role for WWP2 in monocyte cell survival, and this is consistent with lack of WWP2-regulated pathways related to cell death or apoptosis g Representative cellular images (BMDMs) of in-cell IRF7 and p-IRF7 from 10,000 acquired events by imaging flow cytometry (see Methods), showing typical externalized and internalized patterns of colocalized or separately distributed IRF7 and p-IRF7.…”

Bioinformatics Analysis of Competing Endogenous RNA Network and Immune Infiltration in Atrial Fibrillation

“…And studies also have indicated that CCR5 may play a role in Ang II-induced hypertension and vascular dysfunction [ 29 ], as well as in the development of arthrosclerosis and cardiovascular disease [ 30 ]. Additionally, CCR5 inhibition protects against pressure overload-induced cardiac dysfunction through P38 and ERK1/2 signaling pathways [ 31 ]. Therefore, we speculated that CCR5 may be implicated in the pathogenesis of AF through immune and inflammatory responses, which needs to be further explored.…”

Divergent and Overlapping Roles for Selected Phytochemicals in the Regulation of Pathological Cardiac Hypertrophy

“…Of further interest, signal transducer and activator of transcription 3 (STAT3) may be important for interleukin 6-mediated cardiac hypertrophy [ 13 ], which we showed both to be downregulated by baicalein and BHCl. Finally, proinflammatory chemokine ligands, including those with the C-X-C motif (CXCL) and the C-C motif (CCL), have been implicated in cardiac dysfunction and remodeling [ 52 , 53 , 54 ]. Indeed, CXCL-1 was strongly associated with cardiac pathogenesis in angiotensin II-infused mice [ 53 ].…”